There are over one million cases of cancer diagnosed each year in the United States and numerous approaches of therapy including systemic chemotherapy, radiation and surgical resection. Given that systemic chemotherapy and radiation interact with healthy tissue, complications and toxicity often result. Targeted drugs are now being used and produce a lower rate of complications. Ablative approaches, including microwave, radiofrequency and cryogenic therapies have been used; however, these methods are often not selective and tissues and organs surrounding or below the tumor can be affected.
According to the National Institute of Health, 30,640 people were diagnosed with primary liver cancer (hepatocellular carcinoma, HCC) and 142,820 people were diagnosed with colorectal cancer in the U.S. in 2013. Seventy-five percent of these will metastasize to the liver. Liver resection and transplant are the only curative means; however, only small numbers of patients are eligible. Systemic chemotherapy for primary and metastatic tumors in the liver is ineffective, having a response rate of about 20% and a survival benefit of 10.7 months vs. 7.9 months over symptomatic care.
Catheters are commonly used in medicine for delivery of fluids, therapeutics, and implants, and in sampling tissues and bodily fluids. Catheters can be constructed with balloons or other tools to dilate tissue, block fluid flow or isolate segments of the anatomy, such as in treatment of the cancers described above.
Transvascular fluid delivery via arteries or veins is typically used to distribute materials throughout the body and without consideration of a specific target tissue or organ. One notable exception to this is the use of compounds, such as anti-cancer agents that are conjugated to antibodies that target a specific binding site. Anti-tumor agents can also be fashioned to bind to specific cell receptors and block cellular functions of cancer cells. In this way, cytotoxic therapies seek out cancer cells and avoid healthy tissues, reducing systemic toxicity.
However, most drugs are not conjugated or otherwise contrived to seek out a target and drugs that are injected are distributed throughout the body, even though the beneficial effect is limited to one or several target sites. Delivery of drug to non-target sites can cause complications and result in considerable morbidity.
Trans-Arterial Embolization therapy is the transvascular injection of drug and/or embolic agents directly into the tumor vasculature using a microcatheter. Embolization therapy causes a shutdown of blood flow and, when drug or radioactivity is present, simultaneous release of high concentrations of drug or radioactivity. The technique is also noted for its very low level of toxicity.
In the early 1980's, transarterial chemoembolization (TACE) began to be used as a selective cancer therapy. In this method, chemotherapeutic and embolic agents are injected directly into the vasculature of the tumor, a technique that is most common for the treatment of hepatocellular carcinoma. More recently, transarterial radioembolization (TARE) has been used clinically. In this method, radioactive embolic particles, typically yttrium-90 (y90), are injected rather than chemotherapeutic agents. Although the liver is a common target for TACE and TARE, other organs, including, but not limited to, the pancreas, lung, kidney, prostate, stomach, colon and head and neck have been treated using these methods. Chemoembolization was established as a standard of care for intermediate stage hepatocellular carcinoma in 2006.
Numerous studies have demonstrated transarterial embolization to be effective on a number of primary cancers and to have better performance than chemotherapy for both HCC and metastatic colorectal cancers in the liver; however, studies show inconsistent outcomes with reported tumor responses from 15% to 85%. Although anatomical and individual differences are clearly of significance in between-patient variation, clinical studies, each of which include numerous patients, show very different outcomes, indicating that the procedure is not reproducible and that there is little procedural optimization or standardization.
The above procedures are accomplished by inserting a small catheter into the femoral artery at the groin or radial artery of the forearm and navigating it into the liver vasculature, typically the hepatic artery, then into the right or left lobe of the liver or more selectively into particular segments of the liver or super-selectively directly into or adjacent to the tumor. Typically, the tip of the microcatheter is positioned in a supply artery that is proximal to the tumor feeder artery and collateral arteries that branch from the supply artery and flow toward healthy tissues. In this instance, blood flows over the catheter tip and into the tumor and collateral arteries that feed healthy tissues. Injection of embolic agents will follow blood flow and deposit into both the tumor and healthy tissues (non-target embolization). Presently, standard microcatheters, typically at or about 3 Fr, are used to inject antitumor agents into the target vasculature. These standard microcatheters rely on normal blood flow as the means by which the embolic agent moves into the tumor and systolic and/or mean arterial pressure as the packing force. However, as the tumor begins to become embolized, it cannot accept the normal rate of blood flow and intra-tumor pressure rises to a point where the tumor can no longer accept the blood flow and the blood begins to reflux into the tumor feeder and supply artery. At this point tumor embolization can no longer proceed since embolization agents are refluxing out of the tumor along with the blood, even though the tumor is only partially filled with embolic agents. Under these conditions, further injection of embolic agents results in high pressures in the supply artery and a concomitant increase in non-target flow of embolic agents to healthy tissues and reflux backwards over the catheter. This situation also results in loss of an unknown amount of drug which, at least in part, explains the irreproducibility of the technique.
The endpoint of the above procedures is determined by physicians' visual observation of contrast flow and therefore the amount of dose delivered is highly variable. Reflux, non-target embolization in antegrade and retrograde directions, distribution of embolic agents, packing and quantity of dose delivered are variables that can be highly dependent on the rate and pressure of injection, the selection of the type of endpoint, the patient's systolic and/or mean arterial pressure, anatomy and the operator. As such, clinical trials using TACE to treat hepatocellular carcinoma have demonstrated wide variations in tumor response. The most significant clinical problems that occur with the current means of delivery and methods of embolization therapy include inconsistent efficacy and complications from non-target embolization.
Using standard straight-tip catheters, non-target embolization in the retrograde and antegrade directions can be caused when the pressure of injection exceeds the mean arterial blood pressure whereby embolic agents flow into healthy tissues causing complications.
Antegrade
When therapeutic agents are delivered into the vasculature of a target structure using the normal antegrade blood flow to carry the therapy to the target, antegrade non-target flow is unavoidable and injection rate of therapeutic agents must be carefully controlled in relation to the then present flow volume and pressure of blood to avoid an increased amount of antegrade non-target flow and reflux of drug backward over the catheter and into healthy tissues. In particular, when injecting embolic agents into the vasculature of a tumor, pressure distal to the catheter tip continues to increase as embolization progresses, causing a resistance that prevents embolic agents from filling the target vasculature and the possibility of reflux and non-target flow and embolization. It would be desirable to eliminate this antegrade non-target flow and reflux, and the inconsistent dosages that are delivered to targets with current state of the art procedures. It would be further desirable to eliminate the low levels of particle distribution and density throughout the target vasculature. It would be still further desirable to replace current delivery devices that are not always capable of fully isolating the target vasculature and often do not allow the operator to control pressure, flow rate and other parameters associated with therapeutic delivery.
The present state-of-the-art embolization therapy using standard straight-tip microcathetes for tumors in the liver relies on high volume forward flow from the hepatic artery (supply artery) to deliver embolization agents into the tumor. However; as tumor embolization proceeds, larger arterioles and capillaries are filled first, this substantially stopping flow in these vessels which causes: (1) high intra-tumor vascular pressure, (2) high pressure in arteries feeding the tumor, (3) high pressure in the supply artery, (4) reflux over the delivery catheter, (4) increased antegrade non-target flow into hepatoenteric arteries and (5) poor filling and distribution of embolic agents in the tumor. This situation results in an uncontrollable and irreproducible number of particles entering the tumor and high procedural variability.
Problems with the current method of embolization therapy that cause inconsistent outcomes include: high flow rates into the tumor, variable procedural endpoints, unknown quantity of dose delivered, reflux of embolization agents, antegrade non-target flow of embolization particles into branch arteries, rising intra-tumor arterial pressures during the initial stages of embolization, catheter movement during injection, catheter tip position and the catheter not being centered in the blood vessel. The current delivery catheters are unable to control many of the above mentioned variables, producing inconsistent outcomes and making any standardization of the current procedures difficult or impossible to achieve.
The following patents and published patent applications provide some examples of the current state of this art. U.S. Pat. No. 5,647,198 describes a catheter with a pair of spaced apart balloons that define an intra-balloon space. A lumen passes through the catheter and exits within the intra-balloon space allowing injection of drugs, emulsions, fluids and fluid/solid mixtures. A perfusion lumen or bypass extends from a location proximal to the proximal balloon and to the distal tip to allow shunting of blood past the inflated balloons. U.S. Pat. No. 5,674,198 describes a two balloon catheter that is designed for treating a solid tumor. The balloons are positioned to isolate the blood flow into the tumor and allow injection of a vaso-occlusive collagen material to block the tumor blood supply. Clifton et al. (1963) Cancer 16:444-452 describes a two balloon catheter for the treatment of lung carcinoma. The four lumen catheter includes a lumen for independent injection in the space between the balloons. Rousselot et al. (1965) JAMA 191:707-710 describes a balloon catheter device for delivering anticancer drugs into the Liver. See also U.S. Pat. Nos. 6,780,181; 6,835,189; 7,144,407; 7,412,285; 7,481,800; 7,645,259; 7,742,811; U.S. App. No. 2001/008451; U.S. App. No. 2001/0041862; U.S. App. No. 2003/008726; U.S. App. No. 2003/0114878; U.S. App. No. 2005/0267407; U.S. App. No. 2007/0137651; U.S. App. No. 2008/0208118; U.S. App. No. 2009/0182227 and U.S. App. No. 2010/0114021.
What is needed, and not provided by the prior art, are delivery devices and methods that enable exclusive delivery of drug to a target area of the anatomy and elimination or reduction of the flow of drug outside of the target area.